MGY378 26: viral vectors

turnip mosaic potyvirus

• commensalism and symbiosis with droughted plants

  • other viruses also mutualise with insects

• conferred drought tolerance

AAV vectors

• Small, non-pathogenic, infects both dividing and non-dividing cells, long-term expression

• pros: Safe, long-term expression, low immunogenicity

• cons: Limited packaging capacity (~4.7 kb), potential for immune responses upon repeated administration

AAV vector applications

• Leber congenital amaurosis (Luxturna)

• muscular dystrophy

Lentivirus vectors

• Integrates into host genome, infects both dividing and non-dividing cells, long-term expression

• pros: Long-term expression, efficient in dividing cell

• cons: Potential for insertional mutagenesis, complex production

Lentivirus vector applications

• SCID

• CAR-T cell therapy

adenovirus vectors

• High transduction efficiency, wide range of cell types, strong immune response

• pros: High efficiency, robust immune response

  • does not integrate - no side effects

  • high immunogenicity - immune response

  • infects different cell types

  • transgene capacity

• cons: high immunogenicity, limited long-term expression

  • can remove E1 to render it replication-defective

adenovirus vector application

• COVID-19 vaccines

• cancer therapy

gamma-retrovirus vectors

• integrates into host genome, primarily infects dividing cells

• pros: long-term expression, efficient in dividing cells

• cons: risk of insertional mutagenesis, limited tropism

gamma-retrovirus vector applications

• early gene therapy trials

HSV vectors

• large transgene capacity, does not integrate into host genome, crosses blood-brain barrier

• pros: large transgene capacity, reduced mutagenesis risk

• cons: limited long-term expression, potential toxicity

viral vector complications

• immune response risks

• insertional mutagenesis

• toxicity

  • cell damage

  • cytokine release syndrome

• off-target effects

  • unintended tissue effects

  • integration may cause genetic instability/ dysregulation

• germline modification

  • ethics

modifying vectors

• capsid engineering

• reduce immunogenicity

capsid engineering

• enhance specificity and efficiency

• bind specific cell Rs

• better transduction

reduce immunogenicity

• replication-incompetent vectors

• capsid engineering to evade immune system

  • pseudotyped vectors

  • modded surface antigens

• incorporate genes to inhibit imm resp

• choose routes to minimize immune exposure

adenovirus vaccine vector

• high transduction efficiency, strong immunogenicity, large transgene capacity

• cons: high immunogenicity, transient expression, potential side effects

• cases:

  • COVID-19, HIV, ebola vaccines

MVA vaccine vector

• safe, immunogenic, low pre-existing immunity, BSL1

• cons: transient expression, limited scalability

• cases: HIV, Ebola, smallpox

VSV vaccine vector

• replication competence, flexible antigen expression, natural antigen conformation

• cons: neurotoxicity (attenuated versions used), limited human data

• cases: Ebola, HIV, TB

Case study: HIV Ad5 vaccine

• 3 different doses of adenovirus against HIV

• Increased risk to get HIV instead of preventing it

• Adv-5 seropositivity = pre-existing immunity

• Uncircumcised = more target for the HIV to infect

• Inflammatory response against vector stimulating CD4 cells (HIV targets) - increasing the HIV targets

• ADE

  • Neutralizing abs cover up virus and make it not effective

  • For DENV instead of neutralizing, abs decorate the virus and make it have an easier time entering

Case study: HIV RV144 vaccine

• prime-boost

• prime: non-replicating canarypox vector

  • expresses HIV antigens

  • cellular immune response

• boost: protein-based vaccine

  • stimulates ab production

  • humoral response

• efficacy: 31%, increased CD4+ TC responses, enhanced ADCC → protection?

non-medical applications of vectors

• nanotech

• agriculture:

  • virus-induced gene silencing (VIGS)

  • deliver genes to enhance pest and disease resistance

other medical applications of vectors

• cancer: deliver genes to induce apoptosis/ enhance immune response against tumours

• gene editing: deliver CRISPR-cas9

• tissue engineering

ethical considerations

• risk assessment

  • insertional mutagenesis

  • germline transmission

• long-term effects

• informed consent

• global distribution

• cost

Case study: Jesse Gelsinger - adV vector for OTC

• OTC gene problem affecting ammonia metabolism

• use adV vector to deliver corrected OTC gene to liver

• severe immune response, death

• did not disclose previous adverse effects in animal models

• financial interests